This invention relates to the synthesis and measurement of novel benzyl barbiturate derivatives useful as uridine phosphorylase inhibitors in cancer and viral therapies.
It is known in the art that uridine phosphorylase inhibitors possess a number of clinically useful attributes. For example, uridine phosphorylase inhibitors have been proposed as means to increase the selectivity and efficacy of various uracil and uridine derivatives in cancer chemotherapy. In another application (U.S. application Ser. No. 180,525), uridine phosphorylase inhibitors have been proposed recently as rescue agents for reducing the toxicity of antiviral agents such as 3'-azido-3'deoxythymidine (AZT). To be useful, the uridine phosphorylase inhibitors should be potent, specific, and non-toxic, and readily soluble in aqueous solutions buffered within the physiological pH range. In addition, the compounds should also be easy to make and to use.
In the field of cancer chemotherapy, the use of halogenated pyrimidine bases such as 5-fluorouracil (5-FUra), and halogenated pyrimidine nucleosides such as 5-fluoro-2'-deoxyuridine (5-FdUrd) as chemotherapeutic agents is well documented in the art (Heidelberger, C., in Antineoplastic and Immune Suppressive Agents Part II, A. C. Sartorelli and D. G. Jones ed.s, pp. 193-231, (Springer-Verlag, Heidelberg, 1975)). However, the halogenated pyrimidine nucleosides are rapidly degraded to their respective pyrimidine bases, reducing their effectiveness against the cancer tissue they are meant to treat. Moreover, the pyrimidine bases, like 5-fluorouracil, are generally more toxic to the host (non-tumor) tissue.
In recent years investigators have found that uridine phosphorylase inhibitors can increase the efficacy of both chemotherapeutic pyrimidine nucleosides and bases.
In the case of halogenated pyrimidine nucleosides, it is known that the catabolic pathway of these compounds is the same as that of uridine. It is also known that there is little functional thymidine phosphorylase in many tumor cells. As such, the first step in the catabolic pathway in these cells relies primarily on uridine phosphorylase. Inhibiting this enzyme in tumor cells inhibits the catabolism of the agents in tumor tissue, thereby increasing their effectiveness. In host tissue, the halogenated pyrimidine nucleosides can still be catabolized to their pyrimidine counterparts by the action of thymidine phosphorylase.
In the case of halogenated pyrimidine bases like 5-fluorouracil, the agent can compete with cellular uridine and its nucleotides for incorporation into RNA and DNA. However, uridine phosphorylase inhibitors increase the plasma uridine concentration (Monks A. et al., vol. 32, Biochem. Pharmac., pp. 2003-2009 (1983)), and availability of uridine for salvage by host tissue, and increase the tissue pools of uracil nucleotides. The increased intracellular uridine concentration can reduce the toxicity of halogenated compounds in host tissue. Moreover, Darnowski et al. (vol. 45, Cancer Res pp. 5364-5368 (1985)) have shown that the addition of a phosphorylase inhibitor selectively increases the ability of host tissue to salvage uridine. This tissue-specific enhancement of uridine utilization is of particular importance for chemotherapies with 5-fluorouracil.
Another application for uridine phosphorylase inhibitors lies in the protection against host toxicity of antiviral agents. For example, viral therapies for patients infected with the human immunodeficiency virus (HIV), and/or suffering from the acquired immune deficiency syndrome (AIDS), have typically involved the administration of an "antiviral" pyrimidine nucleoside, such as, AZT, (3'-azido-3'-deoxythymidine). These "antiviral" agents function by inhibiting the reverse transcriptase enzyme of the HIV and reducing the cytopathic effects of the virus.
However, the utility of these antiviral pyrimidine nucleosides has been limited by their toxic effects on uninfected cells. Prolonged administration of AZT or related agents can have severe side effects. One common and serious complication of AZT therapy is the suppression of bone marrow growth in the patient (specifically, granulocyte-macrophages and erythrocyte progenitor cells), which leads to severe anemia. This complication has generally limited the dosage or duration of therapy that can be implemented.
Recently, it has been shown that uridine and, to a lesser extent, cytidine can reverse the toxic effects of AZT in human bone marrow progenitor cells (HBMP) without affecting the inhibitory activity of AZT in viral infected cells. See, Somadossi et al., vol. 32, Antimicrob. Agents Chemother. pp. 997-1000 (1988). The mechanism for this "rescuing" ability of uridine is unclear at the present. Unfortunately, because of the body's efficient uridine catabolism, clinical implementation of uridine "rescue" regimens requires administering high doses of uridine. Such high doses can cause toxic side effects, such as phlebitis and pyrogenic reactions.
Viral therapies based on the combination of AZT (or the like) and uridine phosphorylase inhibitors have been suggested by one of the present coinventors and a colleague as an alternative to the uridine "rescue" regimen. See commonly owned, pending U.S. patent application Ser. No. 180,525, filed Apr. 25, 1988, herein incorporated by reference. In this application, uridine phosphorylase inhibitors (UPIs) maintain an effective level of the body's plasma uridine sufficient to "rescue" uninfected cells, without requiring the administration of large doses of uridine.
A number of synthetic uridine phosphorylase inhibitors have been proposed by researchers, including a variety of substituted acyclouridines. See, for example, Niedzwicki et al., vol. 31, Biochem. Pharmac. p. 1857 (1982), and Naguib et al., vol. 36, Biochem. Pharmac. p. 2195 (1987), as well as U.S. Pat. No. 4,613,604, issued to Chu et al.
However, while some of these compounds have proven to be good inhibitors of uridine phosphorylase, many of the acyclouridines are not very water soluble, and in addition, are difficult and expensive to synthesize. Efforts to increase the water solubility of these compounds have met with only limited success (Naguib et al., vol. 36, Biochem. Pharmac. p. 2195 (1987)). Water solubility is essential for practical chemotherapy and antiviral treatments, in order to provide intravenous administration at physiological pH ranges and to allow formulation of reasonable administering volumes. Unfortunately, acyclouridines such as BAU, BBAU, and HM-BBAU are soluble only to about 1 mM in water at room temperature. Administration of a physiologically useful dose can require dilution of these compounds into undesirably large volumes. Although the compounds could be dispersed in an oil and taken orally, this method of administration is not preferred initially, as it is difficult to predict by this method how well the compounds will be absorbed as they will have a first pass effect, i.e., ineffective by oral route. Therefore a need exists for new uridine phosphorylase inhibitor compounds that are easier and more cost-efficient to produce in large quantities, more potent, and more soluble in aqueous solutions.
Accordingly, it is an object of this invention to provide new compounds useful as uridine phosphorylase inhibitors and which can be administered in viral and cancer chemotherapies to reduce toxicity in normal cells. Another object of the invention is to provide a method for reducing the anemia and bone marrow suppression caused by the administration of pyrimidine nucleoside analogues in the treatment of viral infections such as HIV, and HIV-related illnesses such as AIDS, and to provide pharmaceutical preparations for such purposes. Yet another object is to increase the efficacy of cancer chemotherapeutic compounds, as well as to reduce the toxicity of these compounds in normal tissues, and to provide pharmaceutical preparations for these purposes.
These and other objects and features of the invention will be apparent from the description and claims which follow.